Carbonyloxy steroids



United States Patent CARBONYLOXY STEROIDS Jerome Korman, PortageTownship, Kalamazoo County, and John A. Hogg, Kalamazoo Township,Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo,Mich., a corporation of Michigan No Drawing. Application January 26,1954, Serial No. 406,364

9 Claims. (Cl. 260397.1)

This invention relates to a novel class of carbonyloxy steroids, moreparticularly to certain 3-keto-1,4,l7(20)- pregnatriene-Zl-oic acids andalkyl esters thereof and to a process for their production.

The process of the present invention and the novel compoundsthus-produced may be represented by the following formulae:

wherein X is a halogen having an atomic weight from 35 to 127, i. e.,chlorine, bromine, or iodine, wherein R is a substituent from the groupconsisting of a hydrogen atom, an a-hydroxy group, a fi-hydroxy group,an a-acyloxy group, especially lower-acyloxy, e. g., ocacetoxy, a9(11)-double bond, a 9,11-oxido group or a ketonic oxygen (=0), andwherein R is a hydrogen atom or an alkyl radical, especiallyloWer-alkyl, e. g., methyl or ethyl.

According to the present invention 2-halo-3-keto-4,17(20)-pregnadiene-21-oic acid or alkyl esters thereof represented byFormula I is dehydrohalogenated with a dehydrohalogenation agent'toproduce, respectively a 3-keto-1,4,17(20)-pregnatriene-21-oic acid andalkyl esters thereof represented by Formula II. Hydrolysis of an alkyl3-keto-1,4,17(20)-pregnatriene-21-oate (I, R=alkyl) with an acidic orbasic hydrolyzing agent is productive of a3-keto-1,4,l7(20)-pregnatriene-21-oic acid (II, R=H).

Starting steroids for the process of the present invention are2-halo-3-keto-4,17(20)-pregnadiene-21-oic acids and esters thereofrepresented by Formula I. Of these starting steroids, the alkyl3'-keto-4,l7(20)-pregnadiene- 21-oates are preferred, especially whereinthe alkyl' esteris loWer-alkyl, preferably methyl or ethyl, and whereinX is bromine. These starting steroids may be prepared according to themethod disclosed and claimed in application Serial No. 346,274, filedApril 1, 1953, and as disclosed in the preparations hereinafter.

Dehydrohalogenation agents which may be employed include lithiumchloride, potassium acetate, pyridine and the alkyl pyridines, e. g.,the picolines, ,B-lutidines, ,5-

collidines, 'y-collidines, parvulines, parvolines, and the.

like. Of the dehydrohalogenation agents, lithium chloride and sym.'y-collidine, viz., 2,4,6- trimethylpyridine,i

give outstandingly superior results andare the dehydrohalogenationagents of choice.

ice

In carrying out the process of the present invention, the starting2-halo steriod is usually dissolved in the dehydrohalogenation agent, ifit is a liquid solvent for the steroid, or both the dehydrohalogenationagent and the steroid are dissolved in a substantially inert diluent andthen heated, usually at a temperature substantially above roomtemperature, e. g., between about fifty and about 250 degreescentigrade, for about fifteen minutes to several hours, although thereaction ordinarily begins as soon as the heating commences. Since2,4,6-trimethylpyridine is usually selected as the 'dehydroh-alogenationagent, the reaction is usually performed at about the boiling point ofthe 2,4,6-trimethylpyridine, unless an organic diluent is employed.Ordinarily, the dehydrohalogenation agent is employed in a ratio to thestarting steroid of about four to one or greater.

The novel compounds of the present invention are useful in theproduction of A -unsaturated adrenal cortical hormones having modifiedcortical hormone activity, e. g., A -hydrocortisone, A -cortisone, A-ll-desoxyhydrocortisone (17a,21-dihydroxy-1,4-pregnadiene-3,20-dione)and 21-esters therof, e. g., the 21-formate, acetate, propionate,butyrate, cyclopentylpropionate, dimethyl-acetate, trimethylacetate,phenylacetate, phenylpropionate, succinate, benzoate, and the like, ofthese compounds in the same manner disclosed in application Serial No.346,274, filed April 1, 1953, for the production of hydrocortisone,cortisone and Compound S, i. e., protecting the 3-keto group with anenol ether, cyclic ketal, or preferably with a pyrrolidyl enamine, thenreducing the 21-carbonyloxy group with lithium aluminum hydride, lithiumborohydride, or the like, followed by the hydrolysis, usually with acid,of the enamine group to regenerate the A -3-keto group, acylation of the2l-hydroxy group to produce a 2l-acyloxy-1,4,17(20)pregnatriene-3-onecorresponding, other than at the 2'1-posit-ion', to the 2l-carbonyloxysteroids represented by Formula II, and then introducing thel7a-hydroxy-20-keto group by reaction of the thus-produced 21-acyloxysteroid with hydrogen peroxide and a small proportion of osmiumtetroxide, to produce a1.7a-hydroxy-21-acyloxy-1,4-pregnadiene-3,20-dione which is eitherphysiologically active per se or can be converted by known chemicalmeans into the physiologically active adrenal cortical hormones, e. g.,hydrogenating the double bonds and then brominating the 4-positionfollowed by dehydrohalogenation.

Alternatively, the compounds of the present invention can be convertedinto the known estrogenic sex hormones or sex hormone-like compounds bydemethylation of the methyl group attached to carbon atom 10, accordingto methods known in the art, followed by an oxidation of the side chainto produce a 17-keto compound such as, for example, estrone, Il-keto or11a or fl-hydroxy estrone, or methyl ethers thereof, which can beconverted by chemical reduction of the 17-keto group, into thephysiologically active estradiol or methyl ether thereof or intocompounds which possess estradiol-like activity'or can be converted intoestradiol or the methyl ether thereof. A further variation of theconversion of the compounds of the present invention into compoundshaving estradiol-like or adrenal cortical hormone activity canwithlithium aluminum hydride, to produce the corresponding A -3,ZI-dihydroxycompounds followed by the Birch reaction to produce the A -3-keto groupin the A ring. Esterification of the 21-hydroxy group with, for example,acetic anhydride, followed bythe introduction of the 17a-hydroxy-20-ketogroup with hydrogen peroxide and a small amount of osmium tetroxide, isproductive of esters of the physiologically Patented Dec. 18,1956

active IO-normethyl adrenal cortical hormones, e. g.,-normethylcortisone acetate, 10-normethylhydrocortisone acetate and10-normethyl-1l-desoxyhydrocortisone acetate.

The following examples are illustrative of the process and products ofthe present invention which is not to be construed as limited thereto.

PREPARATION 1.2,21-nrErHoxYoxALRYL-1 l-KETOPRO- GESTERONE AND SODIUMDIENOLATE THEREOF Ninteen milliliters (0.136 mole) of ethyl oxalate and21.2 milliliters (0.047 mole) of a 2.2 normal methanolic solution ofsodium methoxide was added to a solution of 6.9 grams (0.021 mole) ofll-ketoprogesterone in 100 milliliters of anhydrous tertialy butylalcohol at about fifty degrees centigrade. The mixture was maintained atroom temperature for three hours, whereafter the precipitated sodiumdienolate of 2,2l-diethoxyoxalyl-llketoprogesterone was filtered, washedwith ether and then dissolved in water. The aqueous solution wasacidified with dilute hydrochloric acid and the thusprecipitated 2,21diethoxyoxalyl 11 ketoprogesterone was filtered therefrom and then driedto yield 10.2 grams, a yield of 92 percent of the theoretical, of 2,21-diethoxyoxalyl-ll-ketoprogesterone in the form of a yellow amorphouspowder which exhibited a reddish color in an alcoholic ferric chloridesolution and had the analysis given below.

Analysis.Calculated for CzsHseOs: C, 65.89; H, 6.87. Found: C, 66.25; H,6.67.

In the same manner as illustrated in the above example, other2,21-dialkoxyoxalyl-1l-ketoprogesterones and their sodium enolates areprepared by the substitution of the selected alkyl oxalate for thediethyl oxalate used in the above example. Compounds thus-preparedinclude those wherein the alkoxy group is lower-alkoxy, e. g., methoxy,propoxy, butoxy, amyloxy, hexyloxy, heptyloxy, octyloxy, and the like.

PREP RATION 2.-2,21-DIETHOXYOXALYL-1lot-HYDROXYPRO- GESTERONE AND SODIUMDnzNoLATE THEREOF In the same manner as described in Preparation 1, the2,2l-diethoxyoxalyl-1la-hydroxyprogesterone and the sodium dienolatethereof are prepared by the substitution of lla-hydroxyprogesterone[Peterson and Murray, I. Am. Chem. Soc., 74, 2381 (1952)] for thell-ketoprogesterone used in the therein-described reaction as thestarting steroid.

PREPARATION 3.2,21-DIETHOXYOXALYL1lfl-HYDROXYPRO- GESTERONE AND SODIUMDIENoLA'IE THEREOF In the same manner as described in Preparation 1, the2,21-diethoxyoxalyl-llfl-hydroxyprogesterone and the sodium dienolatethereof are prepared by the substitution of llfl-hydroxyprogesterone forthe ll-ketoprogesterone used in the therein-described reaction as thestarting steroid.

PREPARATION 4.Z,2l-DIETHOXYOXALYLPROGESTERONE AND SODIUM DIENOLATETHEREOF In the same manner as described in Preparation 1, the2,21-diethoxyoxalylprogesterone and the sodium dienolate thereof areprepared by the substitution of progesterone for the ll-ketoprogesteroneused in the thereindescribed reaction as the starting steroid.Substituting M -progesterone, an llu-acyloxyprogesterone, e. g.,lla-acetoxyprogesterone, or 9,11-oxidoprogesterone, for11-ketopr0gesterone as a starting steroid in the reaction described inPreparation 1, is productive, respectively, of 2,21-diethoxyoxalyl-A-progesterone, a 2,21-diethoxyoxalyl-lla-acyloxyprogesterone, e. g.,2,21-diethoxyoxalylllu-acetoxyprogesterone, and 2,21-diethoxyoxalyl-9,11oxidoprogesterone and the sodium dienolates thereof.

Similarly, the 2,21-di(lower-alkoxyoxalyl) homologues of the compoundsof Preparations 1 through 4 are prepared by substituting the selectedlower-alkyl diester of oxalic acid, wherein the alkyl groups are methyl,propyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, or the like, forthe diethyl oxalate used in the therein-described reactions.

The potassium enolates of any of the above-named 2,21-diethoxyoxalylcompounds or lower-alkoxy homologues thereof are prepared by thesubstitution of potassium tertiary butoxide for the sodium methoxide inthe above-described reactions.

PREPARATION 5.METHYL 2-BR0M0-3,11-DIKET0- 4,17(20)-PREGNADIENE 21 oATE(FROM Iso- LATED 2,21-D1'ETHOXYOXALYL-1 l-KETOPROGESTER- ONE) A solutionof eight grams (0.015 mole) of the 2,21-diethoxyoxalyl-l1-ketoprogesterone obtained according to the methoddescribed in Preparation 1 and 5.9 grams (0.060 mole) of anhydrouspotassium acetate in milliliters of methanol was cooled to zero degreescentigrade in an ice bath and a solution of 7.4 grams (0.046 mole) ofbromine in 74 milliliters of methanol was then added dropwise theretoover a period of about one-half hour to produce2,21,21-tribromo-2,2l-diethoxyoxalyl-11ketoprogesterone. To theresulting mixture was then added about fifty milligrams of phenol and 67milliliters (0.100 mole) of a 1.5 normal methanolic solution of sodiummethoxide whereafter the mixture was heated for five minutes on a steambath followed by the addition of the cooled solution to water. Aflocculent white precipitate of methyl2-bromo-3,l1-diketo-4,17(20)-pregnadiene-21- oate formed, and, afterbeing thoroughly washed with water and dried in a vacuum desiccator,weighed 6.77 grams and melted at 74 to 94 degrees centigrade. 1.50 gramsof this impure product was chromatographed over grams of Florisilmagnesium silicate. The column was developed with ZOO-milliliterportions of solvents of the following composition and order: one ofbenzene, ten of Skellysolve B hexane hydrocarbons plus five percentacetone, and ten of Skellysolve B plus 7.5 percent acetone. The second,third and fourth portions of Skellysolve B plus 7.5 percent acetoneeluates were combined and the solvent was distilled therefrom leaving382 milligrams of product melting at 130 to 154 degrees centigrade.Recrystallization of these crystals from methanol gave analytically puremethyl 2-bromo-3,11-diketo-4,17(20)- pregnadiene-Zl-oate as transparentprisms whose melting point varied between 155 to degrees centigrade and160 to 162 degrees centigrade, depending upon the rate of heating.

Analysis.Calculated for C22Hz7BrO4: Found: Br, 18.46.

In a similar manner, methyl 2-bromo-3,11-diketo-4,17-(20)-pregnadiene-21-oate ester is prepared from other2,21,21-tribromo-2,2l-dialkoxyoxalyl 11 ketoprogesterones wherein thealkyl group of the alkoxy radical is ethyl, propyl, butyl, amyl, hexyl,heptyl, octyl, or the like, by the replacement of the2,21,21-tribromo-2,21- diethoxyoxalyl 11 ketoprogesterone in theabove-described reaction by the selected 2,21,21-tribromo-2,21-dialkoxyoxalyl-l l-ketoprogesterone.

Similarly, other alkyl 2-bromo-3-keto-4,l7(20)p1'egnadiene-Zl-oates,especially lower-alkyl, having at the ll-position hydrogen, an a-hydroxygroup, a fi-hydroxy group, or a ketonic oxygen, are prepared by thereaction of the appropriate2,21,21-tribromo-2,2l-dialkoxyoxalylprogesterone with an alkali-metalalkoxide in an alkanol wherein the alkyl group of the alkali-metalalkoxide and alkanol is methyl, ethyl, propyl, butyl, amyl, hexyl,heptyl, octyl, or the like. Compounds thus-produced include methyl2-bromo-11a-hydroxy-4,17(20)-pregnadiene- 21-oate, methyl2-bromo-11/3-hydroxy-4,17(20)-pregnadiene-Zl-oate, methyl2-bromo-4,17(20)-pregnadiene- 21-oate, the corresponding ethyl esters ofthe abovenamed compounds as well as other lower-alkyl esters.

PREPARATION 6.-METHYL 2-cHLoRo-3,11-DIKETo- 4,17 20)-PREGNADIENE-21-OATE Following the procedure described in Preparation 5,but substituting an equirnolar amount of chlorine for the bromine usedtherein, 2,21-diethoxyoxalyl-1l-ketoprogesterone is converted to2,21,21-trichloro-2,21-diethoxyoxalyl-ll-ketoprogesterone. Reacting thethus-produced 2,21,2l-trichloro-2,2l-diethoxyoxalyl- 1l-ketoprogesterone with sodium methoxide in the same manner as describedin Preparation 5 is productive of methyl 2-chloro-3,11-diketo-4,17(20)-pregnadiene-21-oate.

Similarly, substituting 2,2'1-diethoxyoxalylprogesterone,2,21-diethoxyoxalyl-1la-hydroxyprogesterone, 2,21- diethoxyoxalyl 11phydroxyprogesterone, 2,21 diethoxyoxalyl 11a acyloxyprogesterone, e. g.,2,21 diethoxyoxalyl 11a acetoxyprogesterone, 2,21 diethoxyoxalyl-Aprogesterone, or 2,21 diethoxyoxalyl-9,11- oxidoprogesterone for the2,21 diethoxyoxalyl 1-1 ketoprogesterone used as the starting steroid inthe reaction described in Preparation 5, is productive, respectively, ofmethyl 2 bromo 4,17(20) pregnadiene 21 oate, methyl 2 bromo 1.1a hydroxy4,17(20) pregnadiene 21 oate, methyl 2 bromo 11B hydroxy 4,17 (20)pregnadiene 21 oate, methyl 2 bromo- 11a acyloxy 4,17(20) pregnadiene 21oate, e. g., methyl 2 bromo 11a acetoxy 4,17(20) pregnadiene 21 oate,methyl 2 bromo 4,9(11),17(20) pregnatriene 21 oate and methyl 2 bromo9,11-oxido- 4,17(20) pregnadiene 21 oate.

The 2-chloro analogues of any of the compounds named in Preparations 5and 6 are prepared by substituting chlorine for the bromine used in thehalogenation step of those preparations.

The 2-iodo analogues of any of the above-named alkyl24halo-3-keto-4,17(20)apregnadiene-21-oates are prepared by reaction ofthe selected 2-bromo compound with sodium iodide .and iodine.

Example 1 .-M ethyl 3 -lcet-1 ,4,1 7 (20 -pregnatriene- .271 -0ate Amixture of 0.101 gram (0.2 millimole) of methyl2-bromo-3-keto-4,17(20):pregnadiene-Zl-oate ,and 0.6 milliliter of'y-collidine was heated at the refluxing temperature of the'm'ixture forthirty minutes and then cooled to room temperature. The cooled mixturewas diluted with ether and the 29 milligrams of collidine hydrobromidewhich precipitated was filtered from the solution. The filtrate waswashed with dilute sulfuric acid followed by water and then dried overanhydrous sodium sulfate. The dried solution was freed of solvent andthe oily residue was chromatographed over four grams of alumina. Thecolumn was developed With Skellysolve B hexane hydrocarbons containingincreasing amounts of benzene. The eluate fraction containingSkellysolve B plus 75 percent benzene was freed of solvent byevaporation to give methyl 3 keto l,4,17(20) pregnatriene 21 oate which,when crystallized from a mixture of Skellysolve B hexane hydrocarbonsand acetone, melted at 161 to 170 degrees centigrade. A secondcrystallization from the same solvents raised the melting point of theproduct to 173.5 to 177 degrees Centigrade.

Hydrolysis of methyl 3 keto 1,4,17(20) pregnatriene 21 oate withpotassium hydroxide in a mixture of acetone and Water is productive of asolution of the potassium salt of the free acid which, when neutralizedwith dilute hydrochloric acid, is productive of 3 keto- 1,4, 17 (20)-pregnatriene-21-oic acid.

Example 2.-Mezhyl3,Z1-dikeZ0-1,4,I 7(20)- pregnatriene-Z] -0ateFollowing the procedure described in Example 1, 0.21 gram (0.48millimole) of methyl 2-bromo-3,11-diketo- 4,17 (20)-pregnadiene-21-oatewas reacted with 0.8 milmatographing but after crystallization fromethyl acetate, melted at 209.2 to 218.7 degrees centigrade. Afterrecrystallization from ethyl acetate, the melting point of the productwas raised to 229.2 to 233 degrees centigrade.

Hydrolysis of methyl 3,11-diketo-1,4,17(20)-pregnatriene-21-oate withpotassium hydroxide in a mixture of acetone and water is productive of asolution of the potassium salt of the free acid which, when neutralizedwith dilute hydrochloric acid, is productive of 3,11-dik eto-1,4,17(20)-pregnatriene-21-oic acid.

Example .-Methyl 3-ket0-1 1 u-hydroxy-1,4 ,17 (201- pregnatriene-Z]-0ate Example 4.M ethyl 3-ketO-l 1 fl-hydroxy-I ,4,1 7 (20)pregnatriene-ZI -0afe Following the procedure described in Example 1,methyl 2 bromo 3 keto 11;? hydroxy 4,17(20)- pregnadiene 21 oate isdehydrohalogenated to methyl 3 keto 11/3 hydroxy 1,4,17(20) pregnatriene21- oate by reaction with -collidine.

Example 5.--Methyl 3-ket0-11u-acet0xy-1,4,17(20)- pregnatriene-ZI -0ateSubstituting methyl 2 bromo 3 keto 11a acetoxy-4,17(20)-pregnadiene-21-oate as the starting steroid in the reactiondescribed in Example 1 is productive of methyl 3 keto 11cc acetoxy1,4,17(20)-pregnatriene- I 21-oate as the reaction product.

Hydrolysis of methyl 3-keto-11a-acetoxy-1,4,17(20)- pregnatriene-21-oatewith sodium hydroxide in a mixture of acetone and water is productive ofa solution of the sodium salt of the free acid Which, When neutralizedwith dilute hydrochloric acid, is productive of 3-k6i0-llaacetoxy-1,4,17 (20) -pregnatriene-21-oic acid.

Example 6.Methyl 3-ket0-9,11-oxid0-1,4,1 7(20) pregnalriene-Z] -0ateSubstituting methyl 2 bromo 3 'keto 9,11 oxido-4,17(20)-pregnadiene-21-oate as the starting steroid in the reactiondescribed in Example 1 is productive of methyl3-keto-9,11-oxido-1,4,17(20)-pregnatriene-21-oate as the reactionproduct.

Hydrolysis of methyl 3-keto-9,11-oxido-l,4,l7(20)- pregnatriene-Zl-oatewith potassium hydroxide in a mixture of acetone and water is productiveof a solution of the potassium salt of the free acid, which, whenneutralized with dilute hydrochloric acid, is productive of 3-keto- 9,11oxido 1,4,17(20) pregnatriene 21 oic acid.

Example 7.Methyl 3-ket0-1,4,9(1J ,1 7(20) pregnatetraene-ZI -0ateSubstituting methyl 2-brorno3keto-4,9(11),l7(20)- pregnatriene-Zl-oateas the starting steroid in the reaction described in Example 1 isproductive of methyl 3-keto- 1,4,9(11),17(20)-pregnatetraene-2l-oate asthe reaction product.

Hydrolysis of methyl 3-ket0-1,4,9(11),17(20)-pregnatetraene-Zl-oate withpotassium hydroxide in a mixture of acetone and Water is productive of asolution of the potassium salt of the free acid which, when neutralizedwith dilute hydrochloric acid, is productive of 3-keto- 1,4,9(11),17(20)-pregnatetraene-21-oic acid.

In the same manner described in Examples 1 to 7, the same compoundsproduced therein are prepared by substituting the corresponding 2-chloroor 2-iodo steroid for the methyl 2-bromo-3-keto-4, 17 (20)-pregnadiene-2l-oates employed therein as starting steroids. 1

Similarly, other alkyl 3-keto-1,4,17(20)-pregnatriene- 21-oates,corresponding to the methyl 3-ket0-1,4,17(20) pregnatriene-Zl-oatesprepared according to the procedure described in Examples 1 to 7, areprepared by substituting other alkyl esters for the methyl ester of the2-bromo-3- keto-1,4,17(20)-pregnatriene-2l-oic acids employed asstarting steroids in these examples.

It is to be understood that this invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. 3 keto 1,4,17(20) pregnatriene 21 carbonyloxy steroid represented bythe following formula:

wherein R is a substituent selected from the group consisting ofhydrogen, a-hydroxy, fi-hydroxy, a-lower-hydrocarbonyloxy and ketonicoxygen and wherein R is a radical selected from the group consisting ofhydrogen and lower-alkyl.

2. Lower alkyl 3 keto 11 hydroxy 1,4,17()- pregnatriene-Zl-oaterepresented by the following formula:

3. Lower alkyl 3 keto 1,4,17(2()) pregnatriene- 21-oate represented bythe following formula:

ll OO -10wer-alkyl OH OH: I

4. Lower alkyl 3,11 diketo l,4,l7(20) pregnatriene-Zl-oate representedby the following formula:

References Cited in the file of this patent UNITED STATES PATENTS MarkerOct. 10, 1944 Butenandt May 18, 1948 OTHER REFERENCES Experientia, vol.V, May 15, 1949, p. 204.

1. 3-KETO -1,4,17(20)-PREGNATRIENE-21-CARBONYLOXY STEROID REPRESENTED BYTHE FOLLOWING FORMULA: